U.S. Pat. No. 5,057,614 to Davis, et. al., describes substituted pyrrole compounds of formula I as therapeutically active substances for the use in control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders: wherein R1 signifies hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl or a group of the formula:—(CH2)n—W-Het (a), —(CH2)n-T-C(═V)-Z (b),—(CH2)n—NH—C(═O)-Im (c), or —(CH2)n—NH—C(═NH)—Ar (d)in which Het signifies a heterocyclyl group, W signifies NH, S or a bond, T signifies NH or S, V signifies O, S, NH, NNO2, NCN or CHNO2, Z signifies alkylthio, amino, monoalkylamino or dialkylamino, Im signifies 1-imidazolyl, Ar signifies aryl, and n stands for 2-6; R2 signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl; R3 signifies a carbocyclic or heterocyclic aromatic group; R4, R5, R6 and R7 each independently signify hydrogen, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); with the proviso that R1 has a significance different from hydrogen when R2 signifies hydrogen, R3 signifies 3-indolyl or 6-hydroxy-3-indolyl, R4, R5 and R7 each signify hydrogen, R6 signifies hydrogen or hydroxy and X and Y both signify O and when R2 signifies hydrogen, R3 signifies 3-indolyl, R4, R5, R6 and R7 each signify hydrogen, X signifies (H,H) and Y signifies O; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids; wherein the R3 carbocyclic aromatic group is defined as a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group such as phenyl or naphthyl which can be unsubstituted or substituted with 1 or more, preferably 1 to 3, substituents selected from halogen, unsubstituted C1-7alkyl, hydroxy, unsubstituted C1-7alkoxy, (halo)1-3(C1-7)alkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulfonyl; wherein the R3 carbocyclic aromatic group is selected from phenyl, 2-, 3- or 4-chlorophenyl, 3-bromophenyl, 2- or 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2- or 3-trifluoromethylphenyl, 2-, 3- or 4-nitrophenyl, 3- or 4-aminophenyl, 4-methylthiophenyl, 4-methylsulphinylphenyl, 4-methylsulphonylphenyl or 1- or 2-naphthyl; wherein the R3 heterocyclic aromatic group is defined as a 5- or 6-membered heterocyclic aromatic group optionally fused with a benzene ring and substituted or unsubstituted with 1 or more, preferably 1 to 3, substituents selected from halogen, (C1-7)alkyl, hydroxy, (C1-7)alkoxy, (C1-7)alkyl-halo, nitro, amino, —NH—C(O)—(C1-7)alkyl, —NH(C1-7alkyl), —N(C1-7alkyl)2, —S—(C1-7)alkyl, —C(SO)—(C1-7)alkyl or —SO2—(C1-7)alkyl; wherein the R3 heterocyclic aromatic group is 2- or 3-thienyl, 3-benzothienyl, 1-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or 2-methyl-3-indolyl, 1-methoxymethyl-3-indolyl, 1-(1-methoxyethyl)-3-indolyl, 1-(2-hydroxypropyl)-3-indolyl, 1-(4-hydroxybutyl)-3-indolyl, 1-[1-(2-hydroxyethylthio)ethyl]-3-indolyl, 1-[1-(2-mercaptoethylthio)ethyl]-3-indolyl, 1-(1-phenylthioethyl)-3-indolyl, 1-[1-(carboxymethylthio)ethyl]-3-indolyl or 1-benzyl-3-indolyl; and, when the R3 heterocyclic aromatic group is 3-indolyl, the 3-indolyl nitrogen atom is substituted with a substituent selected from hydrogen, C1-7alkyl, aryl (wherein aryl is phenyl unsubstituted or substituted with 1 or more, preferably 1 to 3, substituents selected from halogen, unsubstituted C1-7alkyl, hydroxy, unsubstituted C1-7alkoxy, (halo)1-3(C1-7)alkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulfonyl), —(C1-7)alkyl-aryl (wherein aryl is phenyl unsubstituted or substituted with 1 or more, preferably 1 to 3, substituents selected from halogen, unsubstituted C1-7alkyl, hydroxy, unsubstituted C1-7alkoxy, (halo)1-3(C1-7)alkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulfonyl), —(C1-7)alkyl(C1-7)alkoxy, —(C1-7)alkyl-hydroxy, —(C1-7)alkyl-(halo)1-3, —(C1-7)alkyl-NH2, —(C1-7)alkyl-NH(C1-7alkyl), —(C1-7)alkyl-N(C1-7alkyl)2, —(C1-7)alkyl-N+(C1-7alkyl)3, —(C1-7)alkyl-NH(C1-7alkyl)NH2, —(C1-7)alkyl-N3, —C1-7alkyl-NH—C(O)—(C1-7)alkyl, —C1-7alkyl-S—C(O)—(C1-7)alkyl, —C1-7alkyl-NH—SO2—(C1-7)alkyl, —C1-7alkyl-NH—SO2-aryl (wherein aryl is phenyl unsubstituted or substituted with 1 or more, preferably 1 to 3, substituents selected from halogen, unsubstituted C1-7alkyl, hydroxy, unsubstituted C1-7alkoxy, (halo)1-3(C1-7)alkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulfonyl), —(C1-7)alkyl-SH, —(C1-7)alkyl-S—(C1-7)alkyl, —(C1-7)alkyl-C(SO)—(C1-7)alkyl, —(C1-7)alkyl-SO2—(C1-7)alkyl, —(C1-7)alkyl-O—SO2—(C1-7)alkyl, —(C1-7)alkyl-O—C(O)—(C1-7)alkyl, —(C1-7)alkyl-C(N), —(C1-7)alkyl-C(NH)—NH2, glucopyranosyl, —(C1-7)alkyl-CO2H, —(C1-7)alkyl-C(O)—O—(C1-7)alkyl, —(C1-7)alkyl-C(O)—NH2, —(C1-7)alkyl-S—(C1-7)alkyl-OH, —(C1-7)alkyl-S—(C1-7)alkyl-SH, —C1-7alkyl-S-aryl (wherein aryl is phenyl unsubstituted or substituted with 1 or more, preferably 1 to 3, substituents selected from halogen, unsubstituted C1-7alkyl, hydroxy, unsubstituted C1-7alkoxy, (halo)1-3(C1-7)alkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulfonyl), —(C1-7)alkyl-S—(C1-7)alkyl-CO2H, —(CH2)2-6—W-Het (wherein W is selected from NH, S or a bond; wherein Het is a saturated, partially saturated or aromatic 5- or 6-membered heterocyclic group optionally fused with a benzene ring and substituted or unsubstituted with 1 or more, preferably 1 to 3, substituents selected from halogen, (C1-7)alkyl, hydroxy, (C1-7)alkoxy, (C1-7)alkyl-halo, nitro, amino, —NH—C(O)—(C1-7)alkyl, —(C1-7)alkyl-NH(C1-7alkyl), —(C1-7)alkyl-N(C1-7alkyl)2, —S—(C1-7)alkyl, —C(SO)—(C1-7)alkyl or —SO2—(C1-7)alkyl; wherein when Het is an aromatic nitrogen-containing heterocyclic group, a nitrogen atom may be substituted with an oxide group; and, wherein Het is selected from imidazolyl, imidazolinyl, thiazolinyl, pyridyl or pyrimidinyl), —(CH2)2-6-T-C(V)-Z (wherein T is selected from NH or S; V is selected from O, S, NH, NNO2, NCN or CHNO2; and, Z is selected from —S—(C1-7)alkyl, NH2, NH(C1-7alkyl) or N(C1-7alkyl)2), —(CH2)2-6—NH—C(O)-1-imidazolyl or —(CH2)2-6—NH—C(═NH)-aryl (wherein aryl is phenyl unsubstituted or substituted with 1 or more, preferably 1 to 3, substituents selected from halogen, unsubstituted C1-7alkyl, hydroxy, unsubstituted C1-7alkoxy, (halo)1-3(C1-7)alkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulfonyl).
U.S. Pat. No. 6,037,475 to Faul, et. al., describes a method of making an N-subsituted indolylmaleimide of formula I as therapeutically active substances for the use in control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders: using an organometallic reagent and an optionally substituted activated organometallic-3-indole maleimide in the presence of a palladium transition metal catalyst wherein R2 is selected from a leaving group and an optionally substituted indol-3-yl, R3 is selected from hydrogen and a protecting group, R7's are hydrogen or up to four optional substituents independently selected from halo, alkyl, hydroxy, alkoxy, haloalkyl, nitro, —NHCO(alkyl), or —NR9R10; where R9 and R10 are independently hydrogen, or methyl, R8 is hydrogen or an optional substituent selected from, alkyl, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group, an alkylglycose residue, or a group of the formula: in which Het signifies a heterocyclyl group, W signifies NH, S or a bond, T signifies NH or S, V signifies O, S, NH or NCN, A signifies alkylthio, amino, monoalkylamino or dialkylamino, and Ar signifies aryl; R16 is hydrogen, alkyl, haloalkyl, acetyl, aryl, —CH(aryl)2, amino, monoalkylamino, dialkylamino, guanidino, —C(═N(alkoxy-carbonyl))-NH-(alkoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl; R14 is hydrogen or an optionally substituted alkyl; or R8 and R14 are linked together through a group of the formula (—(CH2)r—X—(CH2)—) where X is —(C(—(CH2)6—R17)(—(CH2)6—R18))— where R17 and R18 are independently hydroxy, carboxy, acyloxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, cyano, amidino or aminocarbonyl, and n is 1, 2, 3, 4, 5 or 6, p an q are 1, 2, 3 or 4, r is 1, 2 or 3, s is 0, 1, 2 or 3, t is 1 or 2, and u is 0 or 1.
U.S. Pat. No. 5,721,245 to Davis, et. al., describes substituted 4-[3-indolyl]-1H-pyrrolone compounds of formula I: wherein R is hydrogen or hydroxy, R1 and R2 taken together are a group of the formula —(CH2)n— and R7 is hydrogen or R1 and R7 taken together are a group of the formula —(CH2)n— and R2 is hydrogen; R3 is an aryl or aromatic heterocyclic group; R4, R5 and R6 each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl; R8 is a group of the formula —(CH2)p—R9 or —(CH2)q—R10; R9 is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl; R10 is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the nitrogen atom or a group of the formula —U—C(V)—W; U is S or NH; V is NH, NNO2, NCN, CHNO2; W is amino, monoalkylamino or dialkylamino; one of X and Y is O and the other is O or (H,H); Z is CH or N; m, p and q are, independently, an integer from 0 to 5, and n is an integer from 1 to 5, with the proviso that q and m are, independently, 2 to 5 when Z is N; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, as therapeutically active substances for use in control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders.
U.S. Pat. No. 5,624,949 to Heath, Jr., et. al., describes bis-indolemaleimide derivatives of the formula: wherein W is —O—, —S—, —SO—, —SO2—, —CO—, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO—, -heterocycle-, -heterocycle-(CH2)mO—, -fused bicyclic-, -fused bicyclic-(CH2)mO—, —NR3—, —NOR3—, —CONH— or —NHCO—; X and Y are independently C1-C4 alkylene, substituted alkylene, or together, X, Y and W combine to form (CH2)n-AA-; R1 is independently hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR4R5 or —NHCO(C1-C4)alkyl; R2 is hydrogen, CH3CO—, NH2 or hydroxy; R3 is hydrogen, (CH2)maryl, C1-C4 alkyl, —COO(C1-C4 alkyl), —CONR4R5, —C(C═NH)NH2, —SO(C1-C4 alkyl), —SO2(NR4R5) or —SO2(C1-C4 alkyl); R4 and R5 are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2 or 3; and n is independently 2, 3, 4 or 5 as protein kinase C (PKC) inhibitors and as selective PKCβ-I and PKCβ-II inhibitors.
Patent application WO 00/06564 discloses disubstituted maleimide compounds of Formula (I): wherein R1 represents hydrogen or alkyl; R2 represents aryl, cycloalkyl or a heterocycle; R3, R5, R6, R7 and R8 represent each hydrogen, halogen, hydroxy, amino, alkyl or alkoxy; and R4 is W, or R4 and R3 or R4 and R5 may form together a ring substituted by W thereon; wherein W represents —(CH2)l—(Y)m—(CH2)n-Z as PKCβ inhibitors.
Patent application WO 00/21927 describes 3-amino-4-arymaleimide compounds having formula (I): or a pharmaceutically acceptable derivative thereof, wherein: R is hydrogen, alkyl, aryl or aralkyl; R1 is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; R2 is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl; R3 is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkyl wherein the aryl moiety is substituted or unsubstituted; or, R1 and R3 together with the nitrogen to which they are attached form a single or fused, optionally substituted, saturated or unsaturated heterocyclic ring and a method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, dementias such as Alzheimer's disease and manic depression.
The substituted pyrroline compounds of the present invention have not been heretofore disclosed.
Accordingly, it is an object of the present invention to provide substituted pyrroline compounds useful as a kinase or dual-kinase inhibitor (in particular, a kinase selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected from protein kinase C α, protein kinase C β-II, protein kinase C γ or glycogen synthase kinase-3β), methods for their production and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.